NIH Public Access: Adaptive Thermogenesis in Humans

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Int J Obes (Lond). Author manuscript; available in PMC 2013 June 05.
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Int J Obes (Lond). 2010 October ; 34(0 1): S47–S55. doi:10.1038/ijo.2010.184.
Adaptive thermogenesis in humans

Michael Rosenbaum and Rudolph L. Leibel
Columbia University, College of Physicians & Surgeons, Departments of Pediatrics and Medicine,
Division of Molecular Genetics, New York, NY, 10032
Abstract
The increasing prevalence of obesity and its co-morbidities reflects the interaction of genes that
favor the storage of excess calories as fat with an environment that provides ad libitum availability
of calorically dense foods and encourages an increasingly sedentary lifestyle. While weight
reduction is difficult in and of itself, anyone who has every lost weight will confirm that it is much
harder to keep the weight off once it has been lost. The over 80% recidivism rate to pre-weight
loss levels of body fatness after otherwise successful weight loss is due to the coordinate actions
of metabolic, behavioral, neuroendocrine, and autonomic responses designed to maintain body

energy stores (fat) at a CNS- defined “ideal”. This “adaptive thermogenesis” creates the ideal
situation for weight regain and is operant in both lean and obese individuals attempting to sustain
reduced body weights. Much of this opposition to sustained weight loss is mediated by the
adipocyte-derived hormone “leptin”. The multiplicity of systems regulating energy stores and
opposing the maintenance of a reduced body weight illustrate that body energy stores in general
and obesity in particular are actively “defended” by interlocking bioenergetic and neurobiological
physiologies. Important inferences can be drawn for therapeutic strategies by recognizing obesity
as a disease in which the human body actively opposes the “cure” over long periods of time
beyond the initial resolution of symptomatology.
Keywords
Obesity; Adaptive Thermogenesis; Thyroid; Autonomic; Weight Loss
Introduction
Western societies tend to regard obesity, and the inability of individuals to sustain weight
loss, as largely self-imposed conditions which reflect a lack of “will power” related to
lifestyle changes. Optimal levels of adiposity are often defined by cosmetic rather than
medical considerations. However, genetic, epidemiological, and physiological studies
indicate that body fatness/weight is regulated, and that the increasing prevalence of obesity
in western societies reflects the interactions of genes favoring energy conservation and
storage with an environment which enables access to food calories and a more sedentary
lifestyle.
Throughout most of human evolution the tendency to store calories as fat would likely have
conferred an advantage by enabling survival during periods of prolonged caloric restriction,
as well as providing greater energy stores to nourish mother and fetus during and following
pregnancy. Thus, it is likely that the human genome would be enriched for alleles of genes
favoring the storage of calories as adipose tissue 1. Our current environment enables the
Address correspondence to: Michael Rosenbaum, M.D. Division of Molecular Genetics, Russ Berrie Medical Science Pavilion, 6th
Floor, 1150 St. Nicholas Avenue, New York, NY 10032, Tel: 212-305-9949, Fax: 212-304-5210, mr475@columbia.edu.
Rosenbaum and Leibel Page 2
consumption of large quantities of calorically dense foods and the maintenance of an

increasingly sedentary lifestyle. Clearly not everyone has the same “genetic risk” for obesity
and, regardless of any genetic proclivities, anyone will gain weight if they consume more
calories than they expend. As illustrated by diet-induced obesity (DIO)-prone and DIO-
resistant mouse strains 2, as well as humans3, 4, there is a heritable variability in the degree
of weight gain that different individuals will experience in an adipogenic environment. This
variability reflects, in part, heritable influences on how much an individual participates in
such an environment by increasing energy intake and/or decreasing energy expenditure, and
their metabolic responsiveness to an increase in energy intake relative to expenditure 5.
Any change in the amount of energy stored, predominantly as adipose tissue (over 100,000
kcal in a 70-kg man) but also as protein and glycogen, must reflect a difference between
energy taken in as food and energy expended in various forms of metabolic and physical
work (see below). If energy intake and output were not regulated by interlocking control
mechanisms that work concordantly to maintain energy stores, then a very small persistent
change in input relative to output would, over time, lead to substantial gain or loss of stored
calories. Yet, the average U.S. adult gains only 500–1000 g of weight (approximately 2000–
2500 kcal of stored energy) per year (more pronounced in older individuals, African-
Americans, Native-Americans, and Hispanic-Americans) 6, despite ingestion of
approximately 900,000–1,000,000 kcal/year. The remarkable constancy of body weight in
this context, presumably without conscious constant calculation of how many calories are
being consumed and/or expended by most individuals, suggests that energy intake and
expenditure vary directly to maintain relatively stable energy stores 7.
Metabolic responses to attempts to sustain weight loss

In long-term studies of weight-reduced children and adults, 80%-90% return to their
previous weight percentiles 8, while studies of those successful at sustained weight loss
indicate that the maintenance of a reduced degree of body fatness will probably require a
lifetime of meticulous attention to energy intake and expenditure 9, 10. The inability of most
otherwise successfully weight-reduced individuals to sustain weight loss reflects the actions
of potent and redundant metabolic, neuroendocrine, and autonomic systems (see below).
The responses of lean and obese individuals to experimental perturbations of body weight
suggest that the magnitude of stored energy, particularly fat, is defended by central nervous
system-mediated mechanisms that are similar, if not identical in lean and obese individuals.
In both lean and obese individuals, there is potent “opposition” to the maintenance of
reduced body weight that is achieved by coordinated regulation of energy intake and
expenditure mediated by signals emanating from adipose, gastrointestinal, and endocrine
tissues, and integrated by the liver and by central nervous system (see Table 1).
Energy expenditure
Maintenance of a 10% or greater reduction in body weight in lean or obese individuals is
accompanied by an approximate 20%-25% decline in 24-hour energy expenditure. This
decrease in weight maintenance calories is 10–15% below what is predicted solely on the
basis of alterations in fat and lean mass 11, 12. Thus, a formerly obese individual will require
~300–400 fewer calories per day to maintain the same body weight and physical activity
level as a never-obese individual of the same body weight and composition. Studies of
individuals successful at sustaining weight loss indicate that reduced weight maintenance
requires long-term lifestyle alterations 9. The necessity for these long-term changes is
consistent with the observation that the reduction in twenty four hour energy expenditure
(TEE) persists in subjects who have sustained weight loss for extended periods of time (6
months – 7 years) in circumstances of enforced caloric restriction in the biosphere 2

project 13, bariatric surgery 14 and lifestyle modification 15.
Twenty-four hour energy expenditure (TEE) is the sum of resting energy expenditure (REE;
cardiorespiratory work and the work of maintaining transmembrane ion gradients at rest;
approximately 60% of TEE), the thermic effect of feeding (TEF; the work of digestion;
approximately 5–10% of TEE), and non-resting energy expenditure (NREE, energy
expended in physical activity above resting; approximately 30–40% of TEE). The effects of
maintenance of reduced weight on each of these compartments of energy expenditure are
distinctly different. There is no significant decline in TEF following weight loss 11. Some
studies 16–18 report no change in REE following weight loss, while in others the
maintenance of a reduced body weight is associated with modest reductions in REE
accounting for about 10–15% of the decline in TEE beyond that predicted on the basis of
body composition changes 11, 12, 19. The variability in study results probably reflects
differences among studies in multiple factors including degree and duration of weight
stability before and after weight loss as well as changes in subject fitness and time spent in
physical activity following weight loss. Regardless of whether or not changes in REE
account for 10–15% of the changes in TEE following weight loss, NREE is clearly the
compartment of energy expenditure that is most affected by changes in body weight 11, 20
consistent with the importance of physical exercise in the successful maintenance of reduced
weight 9, 21.
The pre-eminence of NREE - accounting for as much of 85–90% of the decline in TEE
below predicted values in weight-reduced subjects 20, 22 could be due to declines in the
actual amount of physical activity performed. In rodents, maintenance of a reduced body
weight is associated with an increase, rather than decrease, in the amount of time spent in
physical activity 23, probably reflecting food-seeking behavior. In-patient and out-patient
studies of humans following weight loss have reported, respectively, no change or as much
as a 30% increase in the amount of time that subjects spend moving each day, 11, 18
supporting the view that skeletal muscle work efficiency is increased 20 (as opposed to
decreased amount of motion per se) following weight loss. Since these effects are most
evident at low levels of work, i.e., those commensurate with activities of daily living, it is
reasonable to infer that some of the opposition to reduced weight maintenance can be
diminished by exercising at higher levels of power output 20, 24.
Studies of skeletal muscle chemomechanical efficiency (calories expended above resting per
unit of power generated) in weight-reduced subjects indicate that maintenance of a reduced
body weight is associated with an approximate 20% increase in skeletal muscle work
efficiency at low levels of exercise, whether measured by bicycle ergometry or 31P-NMR
muscle spectroscopy 20. Ergometric studies measure whole body energy expenditure during
stationary cycling. Energy efficiency is expressed as kcal consumed above REE per unit of
power generated. Fuel utilization (fatty acid vs. glucose oxidation) is assessed by the
respiratory exchange ratio (RER, ratio of CO2 produced to O2 consumed). In 31P-NMR
spectroscopy, the ratio of inorganic phosphate (Pi), which increases during exercise due to
the hydrolysis of ATP, to phosphocreatine (PCr) which decreases during exercise to
replenish ATP, during exercise, reflects the efficiency of muscle in generating a specific
amount of power. In addition, the resting Pi reflects the relative fatty acid to glucose
oxidative potential of muscle, and the phosphocreatine recovery constant (kPCr, a constant
reflecting the exponential rate of PCr resynthesis following exercise as well the maximal
rate of oxygen consumption by muscle) reflects the muscle glycolytic potential 20, 25. 31P-
NMR spectroscopy can also be used to examine the in vivo ATP cost of single muscle
contraction by measuring the PCr depletion rate following muscle stimulation in an ischemic
limb (no PCr repletion until blood flow is restored) 26. Both of these methods demonstrate
that the maintenance of a 10% reduced body weight is associated with an approximate 20%
increase in skeletal muscle chemomechanical efficiency and an approximate 18% relative
increase in the fractional use of free fatty acids as fuel during low level exercise 20, 27 (see
Table 2). These results are consistent with studies of vastus lateralis muscle biopsies in
which the ratio of glycolytic (phosphofructokinase, PFK) to oxidative (cytochrome oxidase)
enzyme activities is significantly decreased following weight loss. The changes in these
enzyme ratios are sufficient to account in statistical analyses for a significant fraction of the
increased efficiency (R2=0.57, p<0.001) and free fatty acid oxidation (R2=0.31, p<0.01) that
occurs during low level-exercise in weight-reduced subjects 27.
Neuroendocrine Function
The neuroendocrine changes associated with the maintenance of a reduced body weight
include increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and decreased
activity of the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal
(HPG) axes. The hypothalamic pro-opiomelanocortin (POMC)-melanocortin-melanocortin 4
receptor (MC4R) pathway, by virtue of its constituent neuronal outflow tracts to the ANS,
neuroendocrine axes, and cortical tracts subserving food intake, may provide a central nexus
for the sum of the integrated effects on energy expenditure and intake that are seen
following weight loss 1, 28, 29.
The importance of the HPA axis in regulating body fat stores is illustrated by the effects of
adrenalectomy on genetically obese rodents. The leptin-deficient or leptin-resistant mouse is

hyperphagic, hypometabolic (much like the weight-reduced human as discussed below),
hypercortisolemic (unlike leptin-deficient and resistant humans), and severely obese. These
phenotypes are abolished by chemical or surgical adrenalectomy 30. Hypercortisolemia
results in loss of lean body mass and increases the partitioning of stored calories to fat 1.
Studies of the HPA axis in which human subjects were assessed following variable weight
loss regimens and lengths of time maintaining a reduced weight have found increases 31,
decreases 32, and no change 33 in indices of cortisol production following weight loss.
Discrepancies among studies may reflect differences in subject populations regarding
exercise, gender, age, or weight loss regimens, as well as the degree of weight stability at the
time of study.
Thyroid hormone increases energy expenditure by increasing heart rate, blood pressure,
muscle ATP consumption (largely by stimulating production of muscle ATPase). The
thyroid hormone deficient patient is hypotensive, bradycardic, and lethargic and tends to
gain weight while the hyperthyroid patient is hypertensive and tachycardic and tends to lose
weight 34, 35. Both weight loss and the maintenance of a reduced body weight are associated
with small but statistically significant decreases in circulating concentrations of

triiodothyronine (T3) and increases in the circulating concentrations of its bioinactive
enantiomer reverse T3 (rT3), suggesting that weight loss results in increased peripheral
conversion of thyroxine (T4) to rT3 36. Thyroid releasing hormone (TRH)-stimulated
pituitary thyroid stimulating hormone (TSH) release is not diminished during caloric
restriction 37 or after weight loss 38 in humans. The lack of increase in TSH with weight
loss, despite the decrease in circulating concentrations of T3, indicates that hypothalamic
TRH release is decreased following weight loss. Caloric restriction and maintenance of a
reduced body weight are associated with decreased circulating leptin concentrations (see
below) 39. Low ambient leptin, in turn, reduces POMC production in hypothalamic neurons.
Decreased hypothalmic alpha-MSH (α-MSH), a proteolytic product of POMC, results in
decreased activity of hypothalamic pro-thyroid releasing hormone (pro-TRH) neurons in
rats 40, thus providing a possible mechanism for the decrease in HPT axis activity following
weight loss and the restoration of circulating concentrations of bioactive thyroid hormones
following leptin replacement 41.
Autonomic Nervous System Function

The autonomic nervous system (both parasympathetic and sympathetic) includes major
outflow tracts linking afferent biochemical signals regarding energy stores and efferent
tracts regulating energy expenditure. Increased parasympathetic nervous system activity
slows heart rate and decreases resting energy expenditure. The sympathetic branch of the
autonomic nervous system modulates feeding behavior, directly increases heart rate, and
acts directly on the thyroid gland to increase the rate of secretion of thyroid hormone 42, 43.
Sympathetic denervation of the arm in humans with palmar hyperhidrosis improves skeletal
muscle work efficiency 44 in arm muscles, and chemical sympathectomy attenuates leptin-
mediated increases in energy expenditure in rats 45. Daily urinary norepinephrine excretion
accounts for a significant proportion of the variance in energy expenditure and its
subcomponents in weight stable subjects 36.
The maintenance of a reduced body weight is associated with significant declines in SNS
tone (by analysis of heart rate following sequential parasympathetic and sympathetic
blockade or 24-hour urinary catecholamine excretion) and increases in PNS tone 36, 43, 46.
Changes in ANS tone associated with weight loss, in particular the decline in sympathetic
nervous system tone, may account for a significant fraction of the hypometabolic state
through direct effects on skeletal muscle, and/or indirectly via effects on circulating
concentrations of thyroid hormones36, 47, 48. Thus, weight-loss mediated changes in
autonomic nervous system activity may constitute a link between weight-loss associated
changes in energy and neuroendocrine homeostasis.
Brown Adipose Tissue

Brown adipose tissue (BAT) allows the uncoupling of mitochondrial substrate oxidation
from ATP production thereby releasing the energy of fatty acid oxidation as heat 49. This is
achieved via a 32kd “uncoupling protein” (UCP1) which is present in BAT, but not in white
adipose tissue (WAT). BAT has a rich sympathetic nerve and vascular supply and, in the
presence of cold, weight gain, and/or sympathetic nervous stimulation in rodents or
exogenous or endogenous hypercatecholaminemia in humans, BAT activity increases
resulting in heat generation 50, 51 The activation of BAT is dependent upon integration of
input from the sympathetic nervous system activation of adrenoreceptors (predominantly
β3) 52, with activation of at least one of the thyroid hormone receptors (TR) subtypes (TRα
or TRβ) 53. The leptin-sensitive declines in sympathetic nervous system activity and
circulating concentrations of bioactive thyroid hormones following weight loss that are
described above constitute a mechanism by which reduced obligatory and/or facultative

thermogenesis by BAT could contribute to adaptive thermogenesis in humans. As little as
25gm of BAT going from a maximally active to a minimally active state following weight
loss would be more than sufficient to account for the magnitude of decline in REE in
weight-reduced subjects that occurs beyond that predicted solely on the basis of weight and
body composition changes 54. Therefore, it is possible that a significant fraction of the
unexplained variance in resting energy expenditure or in changes in resting energy
expenditure following weight loss is attributable to changes in the activity or brown adipose
tissue (BAT) 55.
However, while BAT is a major contributor to adaptive thermogenesis in small mammals 56,
its role in thermogenesis in adult humans remains unclear. In rodents, BAT contributes to
both obligatory thermogenesis (the heat produced to maintain body temperature at rest) and
facultative thermogenesis (the heat produced to maintain body temperature at ambient
temperatures below thermoneutrality) 53. The cold intolerance of hypothyroid rodents

reflects declines in both obligatory and facultative thermogenesis by BAT 53. BAT is easily
detected in rodents and clearly plays a role in non-shivering thermogenesis in human
neonates.
Previous studies showed a lack of a significant presence of BAT in humans except under
extreme conditions of hypercatecholaminemia 57 and, until recently, no studies have been
carried out quantifying the contribution of BAT to total adaptive thermogenesis in humans.
Recent advances in positive emission tomography (PET) scanning technology have allowed
detailed imaging of BAT using uptake of 2-[18F]fluoro-2-desoxy-glucose (FDG) and a
hybrid scanner. FDG uptake has been shown to correspond to the neck, supraclavicular,
mediastinal, paraspinal, paravertebral and renal areas known to contain BAT in
humans 58,59, 60 and FDG uptake in these areas (www.med.harvard.edu/JPNM/chetan/
normals/brown_fat/case.html) is inhibited by β-adrenergic blockade with propranolol 61–63.
In a recent series of papers 54, 64, 65, several groups demonstrated the ability to detect BAT
in healthy human beings with varying results as to whether thermal stimuli are necessary to
detect it. In a retrospective study of [18F]FDG (dose not specified) PET scans, Cypress et
al 54 detected BAT in 7.5% of women and 3.1% of men studied under thermoneutral
conditions. Lichtenbelt et al 64 found that BAT was detected in 23/24 subjects after cold
exposure (16°C for 2 hours) but was not detected in 3 of these subjects who were also
studied under thermoneutral conditions([18F]FDG dose of 74 MBq). Finally, Virtanen et
al 65 reported that BAT was detected in 5/5 adult subjects under both thermoneutral and
post-cold exposure (19°C for 2 hours) conditions using a higher dose (185 MBq) of
[18F]FDG.
The anatomic identification of BAT in humans using FDG does not necessarily reflect actual
thermogenic activity of BAT, and the question remains as to whether BAT actually
participates in resting thermogenesis, diet-induced thermogenesis, or adaptive thermogenesis
following weight loss or gain in humans. Increased glucose uptake by BAT is considered to
reflect increased metabolic activity and thermogenesis 56, 66, 67. This is the basis for the use
of the FDG PET technique in localization of tumors and for the analysis of brain areas
involved in different cognitive activities as well as for examining myocardial metabolic
activity56. Thus, the FDG uptake seen in brown adipose tissue in adult man implies the
existence of thermogenically active tissue in adult man. The magnitude of glucose uptake by
BAT in FDG PET studies of subjects fasted and at rest, compared to other tissues, also
suggests that BAT may play a significant role in glucose disposal in low activity states (i.e.,
the state in which we spend at least 1/3 of our lives). Assuming that reduced BAT activation
following weight loss is a significant factor in adaptive thermogenesis, this effect is more
likely to be evident in obligatory than facultative thermogenesis. In this environment we
spend almost all of our time in thermoneutral conditions reducing the need for facultative
thermogenesis and possibly contributing to the increasing prevalence of obesity 68, 69.
Further studies of the role of BAT in human thermogenesis outside of the neonatal period
are clearly indicated.
Metabolic responses to attempts to sustain weight gain

The metabolic changes that occur in subjects during maintenance of an elevated body weight
following overfeeding involve many of the same systems but are not, in fact, mirror images
of the changes following weight loss. In a manner complementary to that seen following
weight loss, the maintenance of an elevated body weight is associated with significant
increases in circulating concentrations of T3 and T4, SNS tone, TEE, NREE, and, of course,
circulating leptin concentrations and a decreases in PNS tone and skeletal muscle work
efficiency. However, there is no demonstrable effect of the maintenance of an elevated body
weight on circulating concentrations of TSH, and there is a much more marked effect of
elevated weight maintenance on TEF and less of an effect on REE than is seen following
weight loss11, 36, 70.
Unlike the metabolic opposition to sustaining a reduced body weight, which persists long
after weight reduction in mice 71 and humans 72, the increased energy expenditure noted
during short-term overfeeding in mice seems to be short-lived. Rodents with diet-induced
obesity demonstrate increased energy expenditure 73 and increased SNS tone74 during the
first 3–4 weeks of overfeeding. However, after a few months on a high fat diet, these
changes are no longer evident 74, 75, indicating that resistance to sustained increased
adiposity is less sustained than resistance to decreased adiposity 69. The steadily increasing
prevalence of obesity in humans also suggests that body fatness is facilitated more
vigorously than body thinness. In addition to the lack of physiological persistence of strong
metabolic opposition to weight gain, any “defense” against further weight gain is stretched
to the limit by this lifestyle, while opposition to sustaining weight loss remains potent and
viable76.
Energy Intake
As noted above, the long-term constancy of body weight suggests that energy intake and
expenditure vary coordinately to maintain relatively stable energy stores. This “coupling”
which reduces caloric intake in response to decreased energy expenditure is disrupted during
and following weight loss 7. During dynamic weight loss, human beings and rodents are
both hungrier (willing to eat more often) and less satiated (willing to eat more per meal) 77.
Even during maintenance of a reduced weight, satiety remains diminished despite the
decline in energy expenditure 78. The simultaneous declines in both energy expenditure and
satiety following weight loss conspire to create the optimal biological circumstance for
weight regain.
Leptin in Energy Homeostasis

A critical mediator of these reciprocal changes in energy intake and expenditure is the
hormone leptin. Leptin is an adipocyte derived molecule that circulates in weight-stable
individuals in direct proportion to fat mass 79. The hyperphagic, hypometabolic phenotype
of weight-reduced humans is similar to that of leptin-deficient or -unresponsive humans and
rodents 80. Circulating leptin concentrations are inversely correlated with hunger ratings in
humans during weight loss, independent of the amount of weight or body fat lost 81. Leptin
administration reverses the hyperphagia associated with leptin deficiency in leptin-deficient
mice and humans 82, 83, and acts synergistically with sibutramine to reduce food intake in
rodents 84. Leptin suppresses food intake by promoting the production of anorexigenic
neuropeptides (processed products of POMC) and reducing the expression of orexigens such
as neuropeptide Y (NPY), agouti-related peptide (AgRP), and melanin concentrating

hormone (MCH). Thus, decreased circulating leptin concentrations as a result of reduced fat
mass has the net effect of stimulating food intake 1.
The hypothalamic POMC-melanocortin-MC4R pathway is highly sensitive to circulating

leptin concentrations and POMC expression is decreased in low-leptin states 29, 85. Briefly,
POMC is cleaved to alpha-melanocyte stimulating hormone (α-MSH) and beta-endorphin
(β-EP) as well as other bioactive molecules. As discussed previously, α-MSH stimulates
release of hypothalamic pro-TRH. β-EP inhibits the release of hypothalamic corticotropin
releasing factor (CRF). Therefore, reduced ambient leptin induced by weight loss, should be
associated with decreased HPT and increased HPA axis activity. Mice overexpressing the
melanocortin 4 receptor (MC4R) antagonists agouti signaling protein (ASP) or agouti-
related peptide (AgRP) 86- as well as rodents and humans with hypomorphic mutations in
MC4R 87, disruptions of POMC gene expression 88, 89 or of proproneuropeptide (e.g.,
POMC, pro-ACTH, pro-TRH) processing by prohormone convertases 90, 91 - are obese. The
importance of leptin in mediating these effects is reflected in the observation that fasting in
rodents causes hypoleptinemia that is associated with increased arcuate and brainstem NPY
and AgRP mRNA expression and decreased POMC mRNA in lean animals, but not in
leptin-receptor deficient animals 92.
Administration of leptin to leptin-deficient rodents and humans in doses that restore

circulating leptin concentrations to their physiological range increases energy
expenditure 93, decreases energy intake, increases sympathetic nervous system activity 94,
and normalizes hypothalamic-pituitary-adrenal, thyroid, and gonadal function1, 29, 82. Yet, in
humans (lean or obese) and rodents who are not leptin-deficient, induction of weight loss
requires doses of leptin that produce plasma leptin concentrations over 10 times
normal 95, 96. Recent studies of the short-term administration of leptin to weight-reduced
lean and obese subjects suggest that restoration of circulating concentrations of leptin to
levels present prior to weight loss reverses the decreased energy expenditure, and its
associated declines in thyroid hormone and SNS activity and increase in skeletal muscle
work efficiency, and increased energy intake, measured behaviorally and by functional
magnetic resonance imaging of neuronal responses to food, that characterize the weight-
reduced state78, 82, 97. In this sense, the weight-reduced state may be perceived by CNS
components relevant to energy homeostasis as a state of relative leptin deficiency.
Pharmacotherapy activating the leptin-signaling pathway may help weight-reduced
individuals to sustain their weight loss98.
Summary
Attempts to sustain weight loss invoke adaptive responses involving the coordinate actions
of metabolic, neuroendocrine, autonomic, and behavioral changes that “oppose” the
maintenance of a reduced bodyweight. This phenotype is distinct from that opposing
dynamic weight loss per se. The multiplicity of systems regulating energy stores and
opposing the maintenance of a reduced body weight illustrate that body energy stores in
general and fat stores in particular are actively “defended” by interlocking bioenergetic and
neurobiological physiologies. Important inferences can be drawn for therapeutic strategies
by recognizing obesity as a state in which the human body actively opposes the “cure” over
long periods of time beyond the initial resolution of symptomatology.
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Table 1
Changes in energy expenditure, autonomic nervous system function, and neuroendocrine function in subjects
maintaining a reduced body weight with or without leptin “replacement” 1, 97, 99
Effects of 10% Reduced Weight Maintenance Effects of Leptin Administration to Weight-

Reduced Subjects
Energy Expenditure
Twenty-four-hour energy expenditure Decreased (−15%) Reversed
Resting energy expenditure Decreased or unchanged No significant change
Thermic effect of feeding Unchanged Unchanged
Non-resting energy expenditure Decreased (−30%) Reversed
Skeletal muscle work efficiency Increased (20%) Reversed
Autonomic Function
Sympathetic Nervous System tone Decreased (−40%) Reversed
Parasympathetic Nervous System tone Increased (80%) Unchanged
Neuroendocrine Function
Thyroid stimulating hormone Decreased (−18%) Unchanged
Triiodothyronine Decreased (−7%) Reversed
Thyroxine Decreased (−9%) Reversed
Gonadotropins Decreased Reversed
Circulating Leptin Decreased (proportional to fat mass) Reversed

Table 2
Studies of skeletal muscle in weight reduced subjects by ergometry, 31P-NMR spectroscopy, and analysis of
vastus lateralis muscle biopsy specimens 27, 97.
Ergometry 31P-NMR spectroscopy Biopsy
Efficiency NME ↑ 20% at low level exercise. 20% ↑ (Pi/PCr) at low level exercise.
18% ↓ ATP cost/muscle contraction.
Fuel Utilization 19% ↑ in % calories used derived 18% ↑ Pi (FFA/glucose oxidation potential). 12% ↓ PFK (glycolytic) activity,
from FFA oxidation during low No change kPCr (oxidative potential) 17% ↓ PFK/COX (glycolytic/FFA
level exercise oxidative activity)
No significant change in FFA
oxidative enzyme activities
Abbreviations: COX, cytochrome oxidase; kPCr, phosphocreatine recovery constant; FFA, free fatty acids; NMR, nuclear magnetic resonance;
PCr, phosphocreatine; PFK, phosphofructokinase; Pi, inorganic phosphate

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Int J Obes (Lond). 2010 October ; 34(0 1): S47–S55. doi:10.1038/ijo.2010.184.

Adaptive thermogenesis in humans

of metabolic, behavioral, neuroendocrine, and autonomic responses designed to maintain body

consumption of large quantities of calorically dense foods and the maintenance of an

Metabolic responses to attempts to sustain weight loss

months – 7 years) in circumstances of enforced caloric restriction in the biosphere 2

adrenalectomy on genetically obese rodents. The leptin-deficient or leptin-resistant mouse is

with small but statistically significant decreases in circulating concentrations of

Autonomic Nervous System Function

Brown Adipose Tissue

described above constitute a mechanism by which reduced obligatory and/or facultative

temperatures below thermoneutrality) 53. The cold intolerance of hypothyroid rodents

Metabolic responses to attempts to sustain weight gain

Leptin in Energy Homeostasis

as neuropeptide Y (NPY), agouti-related peptide (AgRP), and melanin concentrating

The hypothalamic POMC-melanocortin-MC4R pathway is highly sensitive to circulating

Administration of leptin to leptin-deficient rodents and humans in doses that restore

individuals to sustain their weight loss98.

McGraw-Hill; 2001. p. 3965-4028.

71:1421–32. [PubMed: 10837281]

42. Lang C, Rayos G, Chomsky D, Wood A, Wilson J. Effect of sympathoinhibition on exercise

Rev. 2004; 84:277–359. [PubMed: 14715917]

thermogenesis induced by ephedrine in man. Am J Physiol. 1985; 248:E507–15. [PubMed:

maintaining a reduced body weight with or without leptin “replacement” 1, 97, 99

Effects of 10% Reduced Weight Maintenance Effects of Leptin Administration to Weight-

Resting energy expenditure Decreased or unchanged No significant change

Thermic effect of feeding Unchanged Unchanged

Non-resting energy expenditure Decreased (−30%) Reversed

Skeletal muscle work efficiency Increased (20%) Reversed

Parasympathetic Nervous System tone Increased (80%) Unchanged

Triiodothyronine Decreased (−7%) Reversed

Thyroxine Decreased (−9%) Reversed

Gonadotropins Decreased Reversed

Circulating Leptin Decreased (proportional to fat mass) Reversed

vastus lateralis muscle biopsy specimens 27, 97.

Ergometry 31P-NMR spectroscopy Biopsy

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